One of NIDA's highest priorities for funding is the development of effective pharmacotherapies for substance related disorders. In response to RFA-DA-09-005, soliciting pilot clinical/human studies of interventions that specifically target mechanisms known to play an important role in the etiology of drug addiction, we propose to perform a pilot clinical trial of medication to target a neuromodulator of stress in the CNS, the neurokinin 1 (NK1) receptor system. Based on inferences from recent reports in the scientific literature, the NK1 receptor system is a new potential therapeutic treatment strategy for the cessation of cannabis use in individuals who also smoke tobacco. We hypothesize that the NK1 receptor antagonist, aprepitant, will be efficacious at reducing the withdrawal symptoms, cue craving, and reinforcement value for both cannabis and tobacco resulting from the cessation of either or both drugs. We will assess this hypothesis in the context of a carefully controlled human laboratory study in which subjects (N=108) will be randomized in a 3 x 3 factorial design to one of 3 behavioral conditions: a) withdrawn from both substances, b) withdrawn from tobacco only, or c) withdrawn from cannabis only, and to receive one of 3 medication dose conditions: placebo, low-dose aprepitant (80 mg/day), or high-dose aprepitant (160 mg/day). Medication will be administered for 5 days, followed by a cue challenge, choice procedure, and then a consequence (i.e., oral cannabis or a cigarette or money) also on day 5. The scientific significance is that NK1 receptor antagonists promise to be an important new target for the development of therapeutic medications for treating heavy cannabis smokers. The results of our human laboratory study will lay the foundation for subsequent clinical trials of aprepitant for the treatment of cannabis dependence among individuals who smoke tobacco for the alleviation of either or both concurrent disorders. PUBLIC HEALTH RELEVANCE: The scientific significance of our study is that NK1 receptor antagonists promise to be an important new target for the development of putative therapeutic medications for treating heavy cannabis users who also smoke tobacco. The results of our human laboratory study will lay the foundation for subsequent clinical trials of aprepitant for the treatment of cannabis dependence among individuals who smoke tobacco for the alleviation of either or both concurrent disorders.